Is ERG p.Glu197Lys (c.589G>A) pathogenic?

ERG p.Glu197Lys (c.589G>A) is classified Uncertain significance in ERG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely pathogenic (0.8844); Very rare (popmax 0.000169%, nfe).

How common is ERG p.Glu197Lys (c.589G>A) in the general population?

ERG p.Glu197Lys (c.589G>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ERG p.Glu197Lys (c.589G>A)?

AlphaMissense predicts likely pathogenic (score 0.8844) — an in-silico prediction, not a clinical call.

ERG p.Glu197Lys

c.589G>A · VCV4250669

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8844 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8844	likely pathogenic
REVEL	0.217	benign-leaning
SaProt	LLR -4.83	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 96 kb · p 0.0017 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,980 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,786 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ERG
Protein: p.Glu197Lys
Coding: c.589G>A
MANE Select: NM_182918
Type: single nucleotide variant
Location: chr21:38403509 (GRCh38)
Gene constraint: LOEUF 0.234 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.25 · 8 PDB
Residue 197: the pnt domain

Full ERG gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERG p.Asp363Gly Uncertain significance ★★ ⚠ same type
ERG c.389-2A>G Uncertain significance ★ same type
ERG c.40-56923A>G Uncertain significance ★ same type
ERG c.674-1G>A Uncertain significance ★ same type
ERG p.Ala368Thr Uncertain significance ★ ⚠ same type
ERG p.Ala387Pro Uncertain significance ★ ⚠ same type
ERG p.Ala88Asp Uncertain significance ★ ⚠ same type
ERG p.Arg178Gly Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/erg-p-glu197lys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown